Transcript of Episode 74: Phillip Meade

Disclaimer: Transcripts are automated and may contain errors.

Grant Belgard: Welcome back to the Bioinformatics CRO podcast. Today I’m talking with Dr. Philip Meade, a leadership and culture advisor at Gallaher Edge, whose career has included extensive work inside NASA, particularly around organizational culture and return-to-flight moments after major setbacks. He’s collaborated across public and private sectors and co-authored a book on building high-performing cultures. Today we’ll translate those lessons for labs, universities, biotechs, and pharma, how to evaluate the strength of a culture, diagnose problems, and build habits that last, plus common pitfalls to avoid. Dr. Meade, thanks for joining us.

Phillip Meade: Good morning. Thank you for having me. I’m happy to be here.

Grant Belgard: So we’ll cover three arcs today, your current work and lens, how you got there, including time with NASA, and practical advice for leaders and teams in the life sciences. So to kick us off, in your current work at Gallaher Edge, what kinds of culture or leadership challenges are you most often being asked to help with right now?

Phillip Meade: The thing that we see most often is companies asking us to come in and help them because either they are in the process of growing and scaling or they want to grow and scale and they’ve hit a ceiling and they’re having trouble doing that. And so culture typically is one of those things that either is an enabler for scaling or it ends up being a roadblock that keeps them from being able to do the scaling that they’re wanting to do.

Grant Belgard: When you first meet an executive team, what signals, good or bad, do you look for the first hour?

Phillip Meade: There’s a few things that we typically see that demonstrates what we’re looking for in terms of a high-performing culture. Openness is one of them. Is every member of the executive team truly engaged and contributing or is there one or two key members that are really the ones that are doing everything and everybody else is sort of sitting there waiting and seeing what they do and hanging back? Another one is self-awareness. Are they really aware that when we’re talking about culture that they’re a part of it, that culture starts with them and so that this work is really about them and they’re a piece of it and they’re involved? Or are they talking about everybody else needs to change and this culture is about out there? And then another piece of it that’s very important is a willingness to be vulnerable.

Phillip Meade: Do they show that and demonstrate that willingness to actually let the guard down and take the armor off and be vulnerable as human beings? Or are they armored up and trying to present themselves that way?

Grant Belgard: How do you decide whether a client needs structural changes, leadership, behavioral changes, or both?

Phillip Meade: You know, it’s usually all of the above. It’s just a question of how much of each and how do we set those dials in there. When we talk about organizational culture and how is that created, people take cues for how they behave and what they believe about how they should behave. They take that from the leaders and what the leaders do and what the leaders pay attention to and what the leaders say and do and all of that, as well as from the structure. And so we really want to be intentional about all of that and be intentional about how do we design the behaviors that we want from the leaders and what are the leaders saying and doing, as well as how are we creating the structures and the experiences within the organization that people are seeing and responding to. And so it’s really a total design that we’re looking for from that perspective.

Grant Belgard: Many leaders feel they already talk about culture. What separates talk from traction?

Phillip Meade: I just touched on it a little bit in my previous answer, but first and foremost, it’s an intentional design. I think a lot of people think they’re doing culture just because they do things that are culture adjacent. Like they do things that are around, you know, employees being happy or feeling good in the workplace, but they haven’t done the work to intentionally design what is the culture that they want? How do they create that culture? What are the beliefs that they’re intentionally trying to create in their employees around that culture? And how are they creating those beliefs through the specific experiences that they’re creating? And what experiences are those? How are they doing those experiences? So if you haven’t intentionally designed that, then it is kind of just talk.

Phillip Meade: And so you want to have that level of intentionality to the design of what you’re doing so that you know, let’s just take the silly ping pong table in the break room. If you want to have a ping pong table in the break room, that’s great. Do you know why you have that ping pong table in the break room? You should know exactly why you have that ping pong table there, what that experience is designed to do. Is it what beliefs are you trying to create in your employees? And then what beliefs those are creating? What do those beliefs drive from a behavioral perspective from your employees? And how do those behaviors then help to create that culture and ultimately drive the strategy of your organization? So that’s the whole flow that you want to have from a design perspective. And if you don’t have that level of understanding, then you haven’t really designed your culture.

Phillip Meade: You’ve just bought a ping pong table and put it into your break room. And so it’s there’s nothing wrong with the ping pong table. It’s neither good nor bad, but you haven’t designed a culture around it.

Grant Belgard: What’s your go to way to align executive intent with middle management behaviors?

Phillip Meade: So you want to have first the senior leaders to demonstrate those behaviors, because if the senior leaders aren’t truly living it, it’s going to be very difficult to just look at the middle managers and say, you know, do what I say, not what I do. That never works. Secondly, you’re going to want to communicate those expectations clearly. It needs to be crystal clear so that they understand what is exactly expected of them. You’re going to want to align the systems and processes so that they have the ability to do what you’re asking them to do and that it fits into how they do their jobs and they’re rewarded for it. And then finally, you’re going to want to provide them with if it’s if it’s skills based, you’re going to provide them with training.

Phillip Meade: And if it’s really is behavioral, you’re going to provide them with some behavioral change workshops that will support the behavioral change that you want from them.

Grant Belgard: If a team has strong technical results, but shows strain, missed handoffs, creeping burnout, how do you frame the problem without pathologizing people?

Phillip Meade: This is one of the things that we typically focus on with all of the organizations that we work with, because blame is actually one of the greatest drivers of organizational dysfunction. I mean, you see it in a lot of a lot of organizations, and it’s a huge waste of time and energy. We like to focus on contributions. And so in any time that there’s an issue that happens, there are many things that contribute to it. If you think about blame, blame is typically a game that we play where we try to figure out who was mostly responsible, and then we assign blame to them so that we can say it was their fault. And from an organizational standpoint, if you’re trying to think about how do we become most effective, that doesn’t make us most effective. We really want to figure out how do we diagnose how this happened? How do we correct that?

Phillip Meade: And how do we move forward and prevent this from happening in the future? So the way that we do that is we try to identify all the contributors to the situation, and then we figure out how do we prevent those contributions or shift those contributions so that this doesn’t happen in the future. And so we want to approach it from that standpoint so that people aren’t afraid that if I admit that I contributed to this, either through my action or inaction in some way, I’m not going to be in danger of becoming the person who is blamed as a result. And so we come together and we look. Everybody contributed in multiple ways through action and inaction. The system contributed to it. There were environmental contributors. We really look at exactly all the things that contributed to it, and then we say, okay, how can we shift those contributions in the future and get a different result?

Phillip Meade: And so that’s the way we want to start approaching things differently from now on. How do you design for sustainability so the workout lives the initial consulting period? You really want to embed it within the fabric of the organization. And that’s where, when we talk about true culture change is not a short-term project, this is why. Because oftentimes it can take a little while to really go through the whole process of getting it really embedded. But you want to build it into everything you’re doing.

Phillip Meade: Once you really understand the culture that you’re trying to create and what that looks like and have it well-defined, and you understand the behaviors that you’re looking for, and you understand the core values that you want, and what that really looks and feels like, and how to create this culture that you’re after, then you can build it into how you recruit, how you perform your interviews, how you onboard and introduce people into your organization so that they’re trained into your culture from the beginning. You can build it into your leadership development programs. You can build it into your executive development. You can build it into your performance management systems. You can build it into your succession management. You can build it into the language that you use in your organization and how you talk and speak and interact with each other.

Phillip Meade: And then, as I was talking earlier, you can build it into the experiences that you intentionally design into your organization that are part of the way that you do things as a company. And so, you know, as you’re doing that throughout the course of the year and the course of the life of the organization, you know these are the different experiences we have and why we’re doing it. And you can change those out and tweak those over time. But as you’re doing that, you know what you’re doing and why you’re doing it. And then, as you update it, you know how you’re updating it and why you’re doing that.

Grant Belgard: So, shifting gears to talk about your own career trajectory, what early experiences pointed you towards organizational performance and culture as your focus?

Phillip Meade: Well, you touched on it in the introduction. It was an abrupt change for me. It wasn’t a subtle shift. In 2003, the space shuttle Columbia disintegrated on re-entry, killing all seven astronauts on board. And in the wake of that accident, the Columbia Accident Investigation Board found that NASA’s culture had as much to do with the accident as the piece of foam that hit the wing. And I was asked to lead all of the cultural and organizational changes for return to flight because they grounded the entire space shuttle fleet until we could fix the culture. And so, that really set me off on sort of a life-altering path where I began looking into organizational culture and really how that impacts organizations and how important that is to how they perform.

Grant Belgard: When did you realize engineering, as of course you originally came up as an engineer, right?

Phillip Meade: Yeah.

Grant Belgard: Systems thinking could be applied to human systems.

Phillip Meade: Well, I mean, I will say it was a lifeline to some extent. I was trying to grasp for something to make sense of how do I figure this out? How do I solve for this problem of organizational culture? And I realized that an organization is a system. But the thing that I realized is that it’s not just any kind of system. It’s a complex adaptive system. And so, that’s where systems thinking came in. Because if you try to treat an organization like, you know, a car engine, you’re not going to get the right results. You have to treat it like the complex adaptive system it is. And so, when you shift your thinking and begin, you know, analyzing it and diagnosing it and working with it in that way, you get different results. So, a couple of pivotal mentors that I had, I worked with a couple of consultants very early on, Paul Gustafson and Shane Cragun.

Phillip Meade: They were very instrumental in helping me to learn a lot about organizational behavior. And, of course, I read a ton of books that helped me come up to speed on all of this. And I’ll say that one of the moments that helped shape my approach was really the fact that, you know, I thought that NASA had a great culture. And that’s really part of what freaked me out when I was asked to lead this culture change. Because I would have felt better if there were tons and tons of problems for me to solve. And I didn’t think that there were any. So, one of the moments that shaped my approach was that the results of a study was released right after I was asked to lead this. And it named NASA as the best place in the federal government to work. And it was like, okay, this just confirmed what I thought.

Phillip Meade: And so, it really shaped my approach because it confirmed that the way that we’re looking at culture might not be perfectly correct here. If culture caused this accident, and yet we’re the best place in the federal government to work, then what does culture really mean? And, you know, that’s where I came up with the fact that, you know, culture means more than just people are happy at work, right? It has to mean something more. And so, that really influenced my philosophy on organizational culture.

Grant Belgard: So, this might feed into the next question. What’s a belief you held earlier in your career that you’ve since updated?

Phillip Meade: So, beliefs that I held earlier in my career that I would have updated, I think I’ll go in a different direction on that one. I mean, I was very much an engineer in my early career. I was an electrical engineer. You know, they say you can’t spell geek without double E. And I had, I think one of the ones that is my favorite one to reminisce on is, I used to say, I can explain it to you, but I can’t understand it for you. And, you know, I had philosophies on communications that, you know, if I explained it, and I was technically accurate, and you didn’t get it, then that was your problem. And, you know, I grew a lot, you know, over my early career, realizing that being effective was more important than being right. And being effective meant learning how to work well with other people. And organizational culture, oddly enough, really is a lot about that.

Phillip Meade: Organizational culture is about how do you help human beings to work together effectively as a group. A lot of the psychology underpinnings that we use in the work that we do actually comes from work that was done with the Navy, because they were having challenges, trying to figure out how to put the most effective teams together in the control center of their ships. And their theory was, if we take the smartest, you know, best performer at each position and put them together on these teams, we should get the best performance. And they weren’t getting that. And they were confused. And you would think that that’s what you would get. But in reality, the best performance on a team comes from the teams that work best together, not from putting the best performers together. And so that’s what culture is all about.

Phillip Meade: Culture is about how do you get people and put them together that actually work well together. And in an organization, that’s what you need. You need people who feel good about themselves and have the ability that when you put them together with other people in that environment with other people, they all feel good working together. They feel good about themselves. They have the ability to adapt and interact with each other in ways that it makes the whole team perform better. Not just about each one of them trying to maximize how they work best individually, but the team suffers as a result of it. That’s not what you want as an organization. And so, you know, it’s ironic, but I was a part of that personally when I think back to how I performed individually as a young engineer.

Grant Belgard: So, diving a bit more into your learnings from your time at NASA, when people hear culture, they often picture perks, right? The ping pong table in the break room, as you mentioned. In mission-critical contexts, what does culture actually do?

Phillip Meade: Yeah, so this takes me back to the previous question where I said that, you know, being named as the best place to work in the federal government showed me that it has to mean more than, culture has to mean more than that, right? And so, I define culture as, you know, being three things. I think it has to drive employee engagement because you get so many benefits from that. I mean, when a culture drives employee engagement, I mean, there was a 2020 Gallup poll that said that disengaged employees have 37% higher absenteeism, 15% lower profitability. I mean, that drops down to the bottom line and translates into a cost of 34% of their salary. I mean, you know, engagement is huge. You know, it’s a big deal. And so, having highly engaged employees is a big part of what culture does for you. And then, it also improves people’s lives.

Phillip Meade: And that’s a big part of what having an effective culture does. But the third thing that culture does is that it drives organizational performance and market success. And, you know, for a mission-critical organization like NASA, this means that it had to support mission success, which meant taking astronauts up to space and returning them back to Earth safely. I mean, safety was a huge part of that. And so, if it doesn’t do all three, it’s like, you know, three legs of a stool. If it doesn’t do all three, you don’t truly have an effective culture. I mean, I can think of examples of companies that have any two of those three, and I would argue it doesn’t have what I would call a truly effective culture. In some ways, it’s not doing good things. And so, when it has all three of those, and that’s what it takes to truly have an effective culture, and that’s what you want to be shooting for.

Grant Belgard: What did you learn about surfacing dissent in bad news in environments where schedule pressure and hero narratives play a big role?

Phillip Meade: Yeah. You know, I learned that human psychology is complex. You know, even though we’re an organization full of, NASA was an organization full of engineers, and, you know, we like to joke that they’re not really human beings. They are human beings. And when you talk about organizational culture and what happens there, it all starts inside of the human being, and it really is driven by that human psychology. And we don’t think about this. We don’t talk about it very often in our daily lives, but we’re all actively self-deceiving ourselves, you know, on a daily basis. It’s just, it’s part of what our human psychology does to protect us.

Phillip Meade: And so, you know, when we are afraid of something, when we’re afraid that something’s going to make us feel uncomfortable, when we’re afraid that we’re going to be unpopular, when we’re afraid that this isn’t going to align with the identity that I’ve created for myself, all kinds of funny things happen in our psyche, and we get behavior that you wouldn’t expect. And so, when you’ve got engineers that live in an environment where failure is not an option, and they don’t want to be the one that says that something’s impossible or something that can’t be done, and they’re tremendously committed to mission success, and they love their jobs, and they love doing what they do, and they’re working really, really hard and long hours to try and make something be successful.

Phillip Meade: They don’t want to be the one that holds their hand up and say, hey, I don’t think we can do this, or this isn’t possible, or we can’t get this done. There’s a lot of silent peer pressure to be successful, and to save the day, and to make things work, and to not do that. And it’s not overt, and nobody’s saying anything, and nobody would call them a bad name if they did that, but it’s all below the surface, and it’s all in the subconscious. And so, it makes it very, very hard to identify and see, which is why it’s so deadly. So, many organizations talk about psychological safety and practice what behaviors from senior leaders create or destroy it. It’s really about truly encouraging and rewarding the feedback and dissenting opinions, normalizing dissent and healthy conflict, and helping individuals to increase self-awareness.

Phillip Meade: You know, that self-deception that I was talking about that’s happening on a daily basis, educating people that that’s going on, helping people to know that that’s a piece of what’s happening, and helping us all to know and be aware of what we’re doing and what’s going on so that we can recognize it and combat it. Because noticing is the first step. Until we notice, there’s nothing we can do.

Grant Belgard: Could you share an example of aligning structure, for example, reporting lines or decision rights with the desired cultural behaviors?

Phillip Meade: Yeah. So, there’s two I’d like to talk about. One is sort of a large-scale one, and then there’s another one that I like to use, which is a sneakier one. And so, I like to use it as an example. The larger one was with the Columbia accident. One of the challenges that was identified after the accident was that the way we were structured, the engineering, the technical, as well as the budget and schedule and safety, they all rolled up to the program manager. And so, it was a single point of accountability was managing all of that. And so, there was a feeling like from the engineers that they didn’t have their own voice. And so, you had one human being who was having to try to juggle responsibility for budget pressure and schedule pressure, as well as technical decisions and safety.

Phillip Meade: And so, afterwards, we split that out into separate technical authority and safety authority so that we did have the, again, we called it the three legs of the stool, but we had the three legs there where we had a program manager that was responsible for budget and schedule. And then we had a safety organization that was responsible for safety and a technical organization that was responsible for the engineering. And so, engineering, if they had a technical concern, they felt like they had a route that they could advocate all the way up and didn’t feel like they were having to go up to their boss who was more concerned about budget impacts than the technical concerns. And then the sneaky one that I want to talk about is an organization where they had quality assurance technicians that were responsible for safety and speaking up about safety concerns.

Phillip Meade: And they had to punch a time clock on a daily basis coming in to work. And the engineers that were working in this area didn’t have to punch a time clock. Nobody else had to punch a time clock. And for whatever reason, the quality assurance technicians, the story in their head as a result of punching the time clock was that management didn’t trust them to keep their time, that they distrusted them. And so, that’s the reason they had to punch a time clock. And so, they felt like because they weren’t trusted by management, then they created a similar distrust towards management, because trust is a reciprocal entity. So, if you don’t trust me, I’m naturally not going to trust you. That’s just the way that it works. And so, speaking up and raising safety concerns becomes harder. If I don’t trust management, it’s going to be harder for me to raise a safety concern.

Phillip Meade: And so, it was creating a challenge with raising safety concerns because there was a trust issue. And one of the root causes of this trust issue was this silly time clock that they were having to punch in and out of work. So, it’s just weird structural stuff. It’s all about the beliefs that are created in people through the environment that they live in and through the things that happen. And so, we create those unintentionally many times in ways that we never intended to do.

Grant Belgard: That’s interesting. Yeah. Because in the clinical trial arena, you do have this structural separation of the safety monitoring for the patients, but there’s typically not something like that in the earlier stages of drug development before patients get involved. So, for leaders inheriting legacy systems in history, where do you begin?

Phillip Meade: I always like to begin by trying to learn as much as I can about why things are the way that they are. I don’t like to change things until I understand the reasoning behind why they are and how they got there. Usually, there’s people and there’s inertia around the existing systems and processes and everything. And so, providing honor to why it’s there and being able to respect that and take the good for what it is and then only change the things that need to be changed or build upon what it is. That usually helps at least minimize some of the resistance from the people who are involved in what’s there already. And you can save time and energy too because there’s probably are reasons why things are the way they are. And so, you’re not, you know, breaking things that don’t need to be broken or, you know, doing something that won’t work.

Grant Belgard: If you had a week inside a life sciences organization, how would you diagnose the culture quickly?

Phillip Meade: I would try to be as much of a fly on the wall as I could. I would just try to hang out, visit meetings and listen, see how the meetings go, you know, see how much actual discussion happens in meetings. Are people speaking up? Is there meaningful dialogue and is there healthy conflict happening in those meetings? You know, follow people out into the hallway. Are there, is there more conversation after the meeting than there was in the meeting? You know, listen to what’s happening, the conversations that are happening in the executive meetings and what they’re, they’re asking to have happen. And then, you know, see what the managers at the middle level, what are they telling their people? Are they telling their people the same things that the managers at the upper level are telling? Or is the, does the message get distorted by the time it reaches that level?

Phillip Meade: And do the employees, or do they understand the things that the leaders want them to know? Do they even know why they’re doing what they’re doing? Just that, that kind of a thing. You know, what is, what is the, what is the general vibe around the office feel like, you know, or do employees seem like they’re happy and enjoy being there? Or does it, does it feel like it’s a, it’s a drag hanging out at the office? You can learn a lot just by hanging around.

Grant Belgard: What questions would you ask at the bench level versus the executive level?

Phillip Meade: I probably would ask a lot of the same questions. Honestly, I’d want to know, like, if they understood what their, what their strategy was, it might come out in different language, but I’d want to know, you know, do you understand how you’re going to be successful as a company? What are the values here? Or what, how would you describe the culture? Do you know, do you know what that means to be an employee here? I’d probably ask them questions about how they liked working here.

Grant Belgard: How do you tease apart performance issues that stem from process, structure or relationships?

Phillip Meade: You really just have to dive in and start asking questions and, and, and figure it out. You know, a lot of it is, is trying to figure out, you know, if the person that’s doing it, is it, are they, if there’s a challenge, is it because they, they can’t do it? Or is it because they won’t do it? Do they not have the, the ability to do it because they don’t know how to do it, or they don’t have the ability to do it because there’s something that’s missing? You know, you just have to, there’s just so many different ways it can go. You have to, just have to dig in and, and start asking questions and, and figure things out.

Grant Belgard: For, for regulated environments, of course, drug development is fairly regulated. What cultural strengths and blind spots tend to show up?

Phillip Meade: Well, I mean, sometimes you’ll have a strength from a feeling of, of sameness. You know, there can be like a, a, a sense of community or camaraderie that can come with being a part of a committee or a particular community there. But similarly, a blind spot can come along with that, that maybe there’s an over-reliance on standards or regulations to protect you from things. And, you know, that can be dangerous because many times, well, in all cases, those are only as effective as, as the people who are following them. And so, you know, you, you really have to depend on people to do what those regulations say. So.

Grant Belgard: When, when publication pressure or go, no, go, gates, loom, how do you maintain integrity of decision-making?

Phillip Meade: So first and foremost, I want to be honest, I haven’t dealt with this too much personally, but if I’m reading into the question correctly, I would say that as an organization, you would want to make sure that you are structuring your incentives correctly. You don’t want to create situation where you’re, you’re putting your, your employees into a no-win situation and, you know, putting them under undue, undue pressure to, to do things in order to save their job or, you know, or whatever. So, uh, I think that’s what I would say there.

Grant Belgard: What are the telltale signs that a strong culture has drifted into groupthink?

Phillip Meade: Uh, I think similar to, to what I said about being a fly on the wall in a, in a meeting earlier, you know, groupthink is obvious when everybody basically agrees to everything all the time. So, you know, I, I look for healthy conflict, uh, as a sign of a strong culture in, in many cases. And so I would be looking for, you know, that type of healthy dissent, not arguing or fighting, but, you know, questioning and challenging and, and people with different ideas or different positions on things. And so that’s where you get the, the best decisions and the best ideas and the best innovation. And so, um, that’s what you want to see.

Grant Belgard: What’s your approach to decision rights clarity? Who decides who’s consulted, who’s informed?

Phillip Meade: I don’t think that there’s a single answer to this one because, you know, there’s lots of different types of decisions. The idealistic answer to this is that you want the people who are affected to be involved in the decision. That’s not realistic in a lot of cases. I would say that I would lean as far towards that as is practical because the more that you can involve the people that are impacted in the decision, the more buy-in you’re going to get. And so one of the things that people don’t think about oftentimes is they, they misinterpret what it means to make a decision quickly. And they think of the time to make a decision as the time it takes to actually like decide. And I would argue that the time that you want to look at is the total time from when you start to the time to finish implementation.

Phillip Meade: And so you may get from the beginning to making the decision quickly, but then your implementation may take three times as long if you don’t involve the right people. And sometimes it may take a little longer to get to the actual decision point, but then your implementation is, is a third of the time to actually implement it. So the total time is actually shorter when you involve more people. And, you know, you got to think through that. Obviously you can’t always involve all the people and you can’t, and sometimes it is too long. And the way I just described, it doesn’t work out. And that’s the reason I said, it depends and it’s not really super clear, but, you know, I would lean towards involving more people and trying to get, you know, implementation to go more smoothly and getting greater buy-in when, when you can’t, because it really does, it really does help.

Phillip Meade: And I think that right now, in many cases, people lean too far on trying to decrease the amount of individuals involved because it makes the deciding part go faster. But then I think they’re under, underweighting how much it increases the implementation portion of it.

Grant Belgard: That’s a good point. How do you cultivate leader self-awareness?

Phillip Meade: I mean, coaching is a great way to do that. We have some workshops that, uh, that help to increase leader self-awareness, you know, reading helps, you know, as if once a leader decides that they want to start improving their self-awareness and then there’s, then just starting to pay attention and notice things can, can begin to, to be that part of that process. But as with all self-improvement, it has to start with the desire from the individual themselves to, to improve.

Grant Belgard: So how do you adapt culture work as a company scales from 20 to 200 to 2000, uh, even 20,000, right? Life science organizations come in all shapes and sizes.

Phillip Meade: Yeah. I mean, you’re doing the same basic things. It’s just a matter of how do you roll it out in tiers? So, you know, we, we always like to start at the top and then roll it down. And so you want to start with the executive team and then you want to move down to the layer below that. And then the layer below that. And so you, you just, you have more tiers. It takes a little bit more time. You know, when you start to get up to like 2000 and above, now you’ve got more mature, more well-developed HR departments. So you’re, you begin to work with, you know, more well-developed HR systems and processes. So you’ve got LMSs that you’re, you’re now integrating with and you’re, you’ve got really well-developed performance management systems and tools that you’re integrating into. And you’ve got internal HR teams that you begin to integrate into and work with.

Phillip Meade: And so, you know, you’re, the work that we do begins to integrate with the people that they have and the work that they’re already doing. And so we begin to, to weave in, into that.

Grant Belgard: What’s the best small concrete habit a leader can start tomorrow?

Phillip Meade: You know, for me, it’s, it’s just, I would say it’s, it’s learned something new every day. You know, one of the commitments that I made a long time ago was that I was, I was going to read every day. And so I try to, I try to read something new every day, but I think more generically, I would say just to, to learn something new every day. I think that’s a great habit.

Grant Belgard: What are the top three mistakes leaders make that quietly erode culture over six to 18 months?

Phillip Meade: I think the top three are not communicating, not admitting mistakes and tolerating bad behavior.

Grant Belgard: Where have you seen well-intentioned values backfire?

Phillip Meade: I think there’s two ways that well-intentioned values backfire. The first one is anytime the company or the leaders of the company don’t actually live the values or, you know, do something counter to the values that kills it right there. People see that it’s basically a lie or that it’s not true, then it becomes immediately ignored or, or worthless to them. The other one is when the values as well intentioned as they may be are over general. And Patrick Lencioni refers to these as permission to play values. And I mean, I’m not opposed to them existing as permission to play values, but I would call them that and differentiate those from your true core values. But, and these are things that almost every organization could claim that they have like integrity and respect and safety.

Phillip Meade: You know, it’s, it just feels so vanilla that a lot of times employees will look at those and they’re like, yeah, yeah. Okay. I don’t get it. You know, like it just, it just feels like it’s a platitude or, or something that is just being hung on the wall just to, just to do it because it doesn’t seem like there’s anything particularly special to it. Like, yeah, of course, you know, we don’t want employees to steal from us and, you know, everybody should have some basic respect from each other and you should expect not to die when you come to work. So that, you know, those things make sense. And so people just sort of blow it off that, you know, and they don’t pay attention to it. And so I think that those things are, are very well intentioned and there’s nothing bad to them, but it’s also very difficult to really get a lot of traction with them because they are so in most cases, vanilla.

Phillip Meade: And you know what, what Patrick Lencioni says is that, and unless you can truly argue that you have more integrity than 99% of the other companies in your industry, like it’s not really your core value, like it’s not what defines you. And so it’s, it’s hard to like, say this sets us apart. This is something that we’re going to hang our hat on and your employees see that. And it’s like, okay, like, yeah, we have integrity, but you know, it doesn’t really, it doesn’t really mean, you know, mean something special. And so it sort of just becomes this thing that we hang on the wall.

Grant Belgard: When culture change fails, what was the root cause of that failure most of the time?

Phillip Meade: Most of the time it comes down to a failure of leadership. Usually the leaders, the most senior leaders haven’t really truly bought into it and committed to it.

Grant Belgard: How do you prevent hero culture from undermining redundancy and documentation?

Phillip Meade: This goes back to what we were talking about a little earlier. I mean, this is a self-awareness issue. When hero culture is about me not truly having the self-awareness to realize that I am trying to make myself feel better by becoming the hero. And, you know, it’s that lack of self-awareness. It’s that self, it’s where I, it’s a defensive mechanism where kicking in, where, where I’m just trying to, to prevent myself from, from feeling bad. And so it’s, it’s part of my identity and I’m trying to protect. And so we want to try and raise that and prevent that from happening and increase, increase that, uh, self-awareness so that it, it doesn’t happen.

Grant Belgard: What’s the smallest viable step an individual contributor can take to strengthen culture?

Phillip Meade: The smallest viable step I would say is to increase your courage by 1%. If you increase your courage by 1%, then you’re going to increase your openness by 1%, which means that you’re going to increase the feedback that you give to others by 1%. And you’re going to increase the self-accountability that you have by 1%. And you’re going to increase the initiative that you take by 1%. You’re going to increase the contributions that you make by 1%. You’re going to increase your performance by 1%. I think if, if everybody in the organization were to do that, I think that you’d start to see visible changes in the culture.

Grant Belgard: What book, practice, or question has stayed useful across contexts?

Phillip Meade: I think the thing that has stayed useful across contexts, the practice, I’m going to go with the practice is getting curious. And it’s, it’s something that it’s something that I’ve, I’ve had to learn. And, you know, it’s, I’m not necessarily proud of it, but, you know, one of the things that is my tendency is, you know, and probably a reason why I’m sitting here answering all these questions really quickly for you on a podcast is I like being an answer guy. And so, you know, people come to me and, and ask me a question and I’m, I’m really quick to have an answer. And a practice that I started developing as a leader was to not answer the question immediately and to get curious and to ask more questions and try and learn more and say, okay, well, what’s going on here?

Phillip Meade: Or when someone would say something and I thought that they were wrong or I didn’t, you know, I thought that I had the answer and they didn’t, they were, they didn’t understand, get curious and figure out, well, why do I think that they’re wrong and I’m right? That’s been very, very useful to me across a lot of contexts to just try to get more curious instead of assuming that I always know the answer, that I always had the, you know, the right answer and that everybody else is wrong is very, very useful.

Grant Belgard: So what, what options do our listeners have to get more engaged with you through your work at Gallaher Edge? And, uh, you know, I know you have a book, you offer courses, you have, uh, consulting and so on.

Phillip Meade: Yeah, absolutely. You pretty much summarized it. We have a, we have a book that they can get on Amazon. It’s, it’s called The Missing Links: launching a high-performing company culture. They can get that on Amazon. You can go to our website. It’s Gallaheredge.com and, uh, check us out. Uh, we offer individual workshops as well as, uh, consulting engagements. We have a on-demand leadership development course that we offer. That’s, uh, it’s a micro learning format and, uh, it’s, uh, it’s a great way to get introduced to us and, and see what we did. We’re all about. So a lot of different ways. We, we also do, uh, speaking. So if you’re looking for a speaker for, uh, for an event, it’s another way that we can come and help you all out. So.

Grant Belgard: Great. Dr. Meade, thank you so much for joining us.

Phillip Meade: Thank you, Grant. I really appreciate it.

Transcript of Episode 73: Nataraj Pagadala

Disclaimer: Transcripts are automated and may contain errors.

Grant Belgard: Welcome to The Bioinformatics CRO Podcast, where we talk to scientists, founders, and leaders at the intersection of computation and biology. I’m your host, Grant Belgard. I’m joined today by Dr. Nataraj Pagadala, founder, president, and CEO of LigronBio. LigronBio is a biotech company focused on molecular glue therapeutics, small molecules that co-opt the cell’s own protein degradation machinery to go after proteins that have traditionally been considered undruggable. The company is applying computational chemistry, bioinformatics, and AI-driven platforms like its tri-matrix analyzer to design these glues and target neurodegenerative diseases and other serious conditions where new therapies are badly needed.

Grant Belgard: Nataraj has more than two decades of experience in computational drug discovery, spanning academia and industry from early work in biochemistry and bioinformatics through postdoctoral and research roles, modeling protein structures and aggregates, to senior positions in biotech and now founding his own company. Today, we’ll talk about what he’s working on now at LigronBio, how his career path led him into molecular glues and company building, and the advice he has for students, trainees, and scientists who are now thinking about careers in computational drug discovery, or even starting their own companies. Nataraj, thanks for joining us. Great to have you on the show.

Nataraj Pagadala: Thank you very much, Grant. Thanks a lot for, you know, giving me the great opportunity for the molecular glue audience and also for the targeted protein degradation companies. This is Nataraj Pagadala, founder and CEO of LigronBio, and LigronBio is incorporated in 2023, working on targeted protein degradation space, developing molecular glues for all undruggable targets in oncology side and also in neurodegenerative diseases, mainly focused on Alzheimer’s, and later on it will be extended to Parkinson’s and also ALS therapeutics. So, primarily, we are developing the platform called as the AI TriMatrix Analyzer Platform to rationalize and discover molecular glues for the specific undruggable targets in Alzheimer’s space, and also this is linked with the diagnostic kit, which is called as an L-tag assay.

Nataraj Pagadala: This particular L-tag assay will help in the functional studies of these molecular glues to take it further for preclinical studies and also for clinical trials. So, this is a powerful engine linked with generative AI that will help in discovery of these molecular glues within 36 months.

Grant Belgard: So, for members of the audience who have never heard of molecular glues, what are they?

Nataraj Pagadala: Molecular glues are the small molecules, which is very, all the medicinal chemistry properties are similar to traditional drug molecules, except that the difference between general traditional molecules and molecular glues are these molecules, they do the protein degradation compared to the traditional drug molecules where they inhibit the proteins in the biological system. So, for the undruggable targets, basically, there is no binding pockets where actually these undruggable targets help in the progression of the disease, even though there are the proteins which can be inhibited by the traditional drug molecules. So, that is the reason why these molecular glues are designed especially for the undruggable targets for protein degradation.

Grant Belgard: When you explain your company’s mission to someone with biology background, what do you emphasize first, the disease areas, the modality, or the technology platform?

Nataraj Pagadala: So, basically, our mission is basically to design the molecular glues for any of the disease-specific proteins, which is undruggable mainly. So, at the same time, our mission is to do the targeted protein degradation for the diseases and also help in reduction of the proteins in the biological system and also the disease progression. So, our vision is very broad to develop a molecular glues for all the undruggable targets, you know, and to save the future generations from Alzheimer’s is our very big mission.

Grant Belgard: Are there any currently approved molecular glues?

Nataraj Pagadala: Yes, yeah. So, there is a couple of approved molecular glues. The two are, one is palmolidamide and also one is lenidamide, which is in the market as a revlimid for multiple myeloma. So, and also, it is a very big market for this particular molecular glues for multiple myeloma disease.

Grant Belgard: So, what convinced you that there is space for a new company in this area?

Nataraj Pagadala: So, basically, if you see from the last 10 to 15 years, many companies are developing molecular glues in the targeted protein degradation, but unfortunately, all these companies, they are literally, were not completely successful in developing molecular glues for any disease-specific or also the target-specific because of a lack of a serendipity. So, this is the reason why LigronBio came into picture. We are developing because of, you know, serendipity reasons, you know, to rationalizing the molecular glues and discovery of molecular glues is a very difficult task. So, we are developing right from the scratch. This is the primary reason why we are developing a TriMatrix Analyzer platform where actually this particular platform rationalizes the molecular glues and, you know, for a specific target using a generative AI that will help in discovery one thing.

Nataraj Pagadala: And also, at the same time, this particular platform also, you know, finds out all the off-target interactions, you know, that way we can eliminate all the serendipity problems within the biological system to develop a molecular glue for a specific target without any off-target interactions. That is the reason why LigronBio is a novel compared to all the existing platforms worldwide in terms of, you know, data integration with the AI and also high selectivity and specificity.

Grant Belgard: Neurodegeneration is notoriously difficult. What aspects of those diseases make them feel particularly well-suited for a molecular glue approach?

Nataraj Pagadala: Basically, if you see in the biological system with the neurodegenerative diseases like Alzheimer’s, right? So, that’s what I’m saying that, you know, there are many undruggable targets in the biological system that will help in the progression of the disease, not only in oncology side, but in also the neurodegen, neurological space in the neurodegeneration. So, these, as long as these undruggable targets exist in the biological system, it is very difficult for, you know, to inhibit the progression of Alzheimer’s or Parkinson’s and ALS. So, this is where actually, unfortunately, the targeted protein degradation space is not introduced into this neurological space and people are not successful as of now. So, this is where actually we need to develop these molecular glues and, you know, eliminate these toxic proteins which are undruggable from the biological system.

Nataraj Pagadala: That way, we can slow down the disease progression and, you know, restore the memory function and then also reduce the cognitive decline. So, this is where importance of molecular glues comes into picture with respect to neurodegenerative diseases.

Grant Belgard: How do you balance going deep on a few carefully chosen targets versus exploring widely across many possible targets with your platform?

Nataraj Pagadala: So, basically, this particular platform designs the molecular glues for any specific target. So, even though there is no three-dimensional structures of the protein done by crystallography or by any other method. So, this particular platform designs the molecular glue just by the amino acid. So, basically, if you see the undruggable targets, then there is a motif called, let’s say, degron. So, this degron is a six to seven amino acids or maximum 10 amino acids. So, based on that, this particular platform designs the molecular glue based on the amino acid. So, it is even the layman who doesn’t know how to design the molecular glues, this particular platform gives an opportunity just by typing, inputting the amino acid, amino, just an amino acid or a peptide sequence, it will develop a molecular glue.

Nataraj Pagadala: That’s where this particular platform is completely different from all the existing platforms worldwide.

Grant Belgard: What kinds of collaborations or partnerships are most important for a company like yours at this stage?

Nataraj Pagadala: So, at this stage, particularly because, you know, the experiments of targeted protein degradation is different than the traditional way. So, that is the reason why we need partnerships, you know, who are well-versed with the targeted protein degradation space. So, this is where, actually, we need the partners like BMS who is working on targeted protein degradation or also C4 Therapeutics or Chimera Therapeutics. You know, these companies are developing or working on a protein degradation, but unfortunately, they are not working especially on molecular glues, but they are working on other modality called as a protag. But, you know, there are some companies who are working on especially on molecular glues, but, you know, they were not successful as of now.

Nataraj Pagadala: So, we can help those kind of companies, you know, we can help, we can also partner with those companies to design the molecular glues with this particular platform and also help them to, you know, for the targeted protein degradation with the molecular glues with our platform. That’s where, you know, we can partner with those companies and we also, we can help those companies for developing a molecular glues.

Grant Belgard: When you think a few years ahead, what would success look like for LigronBio?

Nataraj Pagadala: Earlier, a few years ahead, right? You know, that time, actually, to be honest, funding is much flexible compared to this particular time where, you know, funding is a very bit hard. So, because of not successful by many of the companies. So, otherwise, you know, by today, LigronBio might have developed the molecular glues for the Alzheimer’s therapy. And by today, we might have at least reached the patients, you know, clinical trials for Alzheimer’s therapy and also might reach the patients.

Grant Belgard: And is the vision to accomplish that through partnerships or are you planning on sponsoring trials as Ligron?

Nataraj Pagadala: Yeah, actually, we are also trying to do from our side, our own clinical trials. At the same time, we are also looking for the big partners. You know, once we complete the initial phase of studies, once we file the IND, then we are also looking for the big partners to step in and also do the clinical trials, you know, as a joint collaboration with LigronBio.

Grant Belgard: What do you see as the main advantages and disadvantages of molecular glues compared to more traditional small molecule approaches?

Nataraj Pagadala: The most important advantage of molecular glues is, you know, because this is an event-driven mechanism, the effectivity and also the degradation therapy is more effective for any disease compared to the inhibition. That is a major difference between the molecular glues and also the traditional inhibitors because the traditional inhibitors are an occupancy-driven mechanism. So, as long as you take the drug molecule, then the effect will be more on the disease state. But when in the molecular glues, even though the molecular, the drug will be eliminated from the biological system, then still the effect will be more. So, that is the reason why, if you see the efficacy is also very high when compared to traditional molecules, and the effect will be 100 times more than the traditional drug molecule.

Nataraj Pagadala: So, that is the reason why, and not only that, basically, the molecular glues are treat undruggable targets, which is notoriously undruggable in the biological system and helps the disease progression. As long as these, as I said, you know, earlier that these proteins are not eliminated from the biological system, the disease progression will still be there. That is the reason why we cannot stop oncology, we cannot, cancer progression, and also neurodegeneration. So, there actually, traditional methods cannot deal with those undruggable targets. Only molecular glues can help in that particular situation and, you know, help in the inhibition of disease progression.

Grant Belgard: What makes designing molecular glues hard, scientifically or computationally?

Nataraj Pagadala: Basically, I see, basically, as I said, you know, the molecular glues, they influence the target protein based on a simple motif, which is called as a degron. So, degron is always, you know, as I said, you know, maximum of 10 amino acids, right? So, this is not a catalytic site. This is a catalytic site for our traditional drug molecules is different than, you know, influencing the drug molecule based on this particular glue, which is a solvent exposed. So, you know, to formation of ternary complex is very, very difficult with respect to molecular glues. So, this is where the difficulty comes in, one thing, because as I said, you know, the degron is only 10 amino acids or maximum of 6 amino acids. So, there will be serendipity of the molecular glues because, you know, most of the kinases, you know, most of the kinases contains this kind of a degron where, you know, 6 to 7 amino acids.

Nataraj Pagadala: That is the reason why there is a high chances of off-target interactions with the molecular glues. That’s where we need to eliminate those molecular glues. And the AA TriMatrix Analyzer platform is the one that, you know, eliminates all these off-target interactions and gives them highly specific molecules for the time, you know, that shows a target protein degradation.

Grant Belgard: How do you think about modeling ternary complexes and cooperativity when you’re working with molecular glues?

Nataraj Pagadala: So, modeling, basically, as I said, you know, we are training a very big database of ternary complexes right from the literature and also from our own in-house experimental studies. And we are also, you know, mapping the proteome in the biological system for all the undruggable targets, you know. So, that will help us in, you know, to see that using a generate AI, artificial intelligence, you know, large language models, that will help us, you know, to see that, you know, how the molecular glues is especially, you know, seeing the off-target interactions. Once we eliminate that off-target interactions, it is easy for designing of molecular glues for a specific target. So, this is where actually that we are building the TriMatrix Analyzer platform.

Nataraj Pagadala: And also, because, you know, most of the targets doesn’t have a three-dimensional structure, this is where another advantage of this platform is that even though there is no three-dimensional structure, still we can develop a molecular glue for the particular target, you know, just based on amino acid as an input. So, this is where the advantage of this one, and also the difficulty that I said, you know, in most of the companies, they don’t have a three-dimensional structure, you know, for most of the targets, you know, unless there is no three-dimensional structure, there is no molecular glue. But a TriMatrix Analyzer platform can do this. And at the same time, most of the companies, to find out a ternary complex formation, they are using a diagnostic kits. Those diagnostic kits is based on the fluorescence.

Nataraj Pagadala: They only give indication about, you know, whether the ternary complex is formed or not. But when that is taken into experimental site, then it is not replicated. The diagnostic kit is not replicated. The results of the diagnostic kit is not replicated in the biological system in most of the cases. But we are developing a diagnostic kit in, which is called as an LTG assay, which gives information about, you know, how the ternary complex is formed, which is like an alternative to x-ray crystallography. That’s where we can clearly see that how the ternary complex is formed. So, this is where the difficulty from all the big companies are facing as of now. And that’s what we want to make it easier for all these companies, with our TriMatrix Analyzer platform, or also the diagnostic kit.

Grant Belgard: How do you decide which parts of the problem to treat with more traditional physics-based structural biology approaches versus more data-driven AI-ML approaches?

Nataraj Pagadala: So, basically, in the physics-based approaches, you know, most of these approaches are for traditional therapy for all the proteins which have a three-dimensional structure of the protein, right? You know, on the catalytic side, you know, there it is easy for the physics-based approaches, you know, for designing of the drug molecules. But data-driven approaches, this where actually, where we don’t have a proper [trim?] structures of the protein, this is where actually the data-driven approaches comes into picture. Now, just like, as I said, you know, for all the undruggable targets where we need lots of data, and lots of data to develop one molecular glue for a specific target.

Nataraj Pagadala: This is where AI and also machine learning and artificial intelligence comes into picture compared to, even though, basically, artificial intelligence and machine learning is also useful for traditional therapy, but especially because that even though artificial intelligence and machine learning is not needed, still we can develop a drug molecule for the proteins which have three-dimensional structures of the protein and also the catalytic pockets. But without the data-driven approaches and without AI and ML, it is very, very difficult to design molecular glue for undruggable targets.

Grant Belgard: How important is experimental feedback for your models and what does that loop look like in practice?

Nataraj Pagadala: Basically, the experimental studies is very important because, you know, the important thing is, you know, very, very rare that we see the targeted protein degradation effectively by molecular glue in the beginning. So, the experimental side is very, very important. I know because, you know, there are many factors that we need to find out in the area of targeted protein degradation, especially with the molecular glues, because, you know, the protag development is completely different. So, it is easy to find out the targeted protein degradation with the protags. But molecular glues is a small molecule and they influence the target protein through small motif. Sometimes, you know, we don’t know how the degradation is happening, you know, how the degradation is happening, whether the territory complex is formed. You know, this is a very complex system through molecular glues.

Nataraj Pagadala: That is the reason why the experimental data, not only that, you know, it’s like, you know, if you check, you know, thousands of, hundreds of molecular glues, sometimes, you know, we end up with no molecular glue showing a targeted protein degradation. So, that is where experimental data, one experimental data, and one targeted protein degradation will give a clue for many, many stages of a molecular glue development in the biological system.

Grant Belgard: Where do you see the biggest gaps right now in this space? If you could choose one particular type of data to just have a lot more of, or better data of, what would that look like?

Nataraj Pagadala: So, basically, I see the main gap here is, especially in the molecular glue is, you know, we don’t have a ternary complexes. So, that is where actually we cannot design a molecular glues, the ternary complexes, not only, and also from x-ray crystallography, especially from the x-ray crystallography, actually, how the ternary complexes formed, except, you know, five or six cases. Not only that, you know, because when these undruggable targets, you know, the ternary complexes formed, it’s a larger, you know, it’s a very big complex. It’s very difficult sometimes to create a three-dimensional structures of the proteins through the x-ray crystallography because of its complexity in nature. So, this is where actually the difficulty is coming from in the area of molecular glues.

Nataraj Pagadala: That’s where we need to do some computational studies in the beginning with enormous, generate enormous amount of data, what the ternary complexes, you know, mapping of all the ternary complexes. That’s where we get some clues to do the experimental studies. If it is replicated, then we can say that, you know, yeah, this is what is happening from my computational studies, and this is also replicated in experimental studies. Then from that, you know, generate more, you know, molecular glues for other targets, you know, more data-driven through AI and ML.

Grant Belgard: So, to talk about your career, looking back, what were the big inflection points that shaped your career in computational drug discovery?

Nataraj Pagadala: Basically, I did my PhD in computational chemistry in 2007. And after that, you know, I did four years of postdoc in the University of Alberta and one year of postdoc in Belgium in KU Leuven University. So, I have lots of my career, you know, 25 years of experience. But, you know, all my career, I worked on a traditional way, you know, developing a drug molecules for all the proteins, for all the proteins which has the binding pockets, you know, have a very great traction record of computational drug discovery from the last 25 years, you know, published for international publications. And also, I was also rated as one of the eminent scientists in computational chemistry by Carnegie Mellon University. So, you know, but unfortunately, I never worked on this targeted protein degradation earlier, before I started my career in [biotherics], you know.

Nataraj Pagadala: There, my journey of a targeted protein degradation has changed, actually. Yeah. So, from there, you know, after going in-depth analysis, you know, then I realized that, you know, this is a, it’s not a simple thing, you know. I need to, I need to show to the world that, you know, with all my experience that, you know, how can we design the molecular glues? How can we not only molecular glues, you know, how can, I know, targeted protein degradation can be done easily? That is the reason why I started this particular career. That’s where the, I know, the inflection point has come in my career to show to the world that, you know, how can we do this? Not only that, with the doing of this, now, how can we, you know, reduce the progression of the Alzheimer’s or Parkinson’s and also ALS and also major this, this devastating diseases, you know.

Nataraj Pagadala: With this technology, we can definitely protect the future generations because we know that COVID-19 has, you know, pandemic has created, you know, havoc in entire world, right? You know, half of the world was got wiped off. So, that is the reason why I changed my career that I want to do something to this, you know, in the disease therapy and I want to show something to this, you know, how can we, you know, stop the diseases or also we can, we can inhibit the disease progression and, you know, protect the future generations for, for these devastating diseases.

Grant Belgard: What gave you the confidence to start your own company doing this?

Nataraj Pagadala: So, basically, my experience, you know, from the last 25 years, as I said, you know, I have a great track record of, you know, computational drug discovery and also because, you know, as I said, you know, I, I did a full five years of postdoc in a PhD and publications, you know, my, as from Carnegie Mellon University, I was also rated as an eminent scientist. So, based on my career, my track record and my way of doing a drug discovery, so it’s completely, a little bit different, you know, compared to other people in terms of thinking, in terms of implementation. That gives me confidence that, you know, definitely my approach will help definitely for these diseases to, for the disease progression, inhibit the disease progression.

Nataraj Pagadala: So, that is the reason why with all my computational chemistry, because not only that, you know, my other confidence is because I’m a, I’m a biochemistry background. Mainly, my, my background is biochemistry with a genetics, you know, with a PhD genetics department. And also, I’m well-versed with molecular biology and all the biology aspects. So, that’s where actually, I can easily connect my biochemistry experience with a computational chemistry experience, with a drug discovery experience, and also experience in biophysics. So, with all these subjects, you know, great expertise, it is easy for me to design the molecular glues. Think about how the drug molecule works in the biological system. That’s where I can easily connect. That’s where my confidence has come that, you know, I can achieve, not only that, you know, I don’t need big laboratories to develop these drug molecules.

Nataraj Pagadala: You know, I can sit at home and design the molecular glues in on the computer with all my expertise. So, that’s where, you know, I started, I started this company because of all my expertise and also discovery of these drug molecules without having a laboratory spaces.

Grant Belgard: Have there been any particularly helpful pieces of advice from other founders or mentors that have changed the way you run the company?

Nataraj Pagadala: Actually, because, you know, there are very less people, you know, who are working on molecular glues. So, and as of now, apart from the very big companies, like [?], and also C4 Therapeutics, and also Chimera Therapeutics, and BMS, apart from this, I personally feel that, you know, I’m the only one who started as a startup with developing a molecular glues and developing a platform. Other than this, you know, till now, I did not see any kind of other founder developing a molecular glues till today.

Grant Belgard: What’s something about the founder-CEO role that you didn’t appreciate until you were actually doing it?

Nataraj Pagadala: Yeah, actually, as I’ve basically, you know, earlier, when I was doing, working in different companies, you know, at that time, I was, you know, my ideas was not taken into consideration. But as a CEO of the company, when I was developing this TriMatrix Analyzer platform, when I was developing this, you know, designing the molecular glues, you know, with a diagnostic kit, you know, that’s where actually people completely, you know, seeing me as a different person in terms of, because, you know, there are people who are well worth the experience from the last 10 to 15 years of experience. Even though they have so much of experience, they were unable to figure out how the ternary complexes, how the targeted protein degradation is happening in the biological system, you know.

Nataraj Pagadala: But as a CEO of the CEO of LigronBio, as within a short period of time, you know, when I was doing this, you know, then people, you know, are seeing me as a different exceptional person and then who can definitely deal these particular problems, you know, help the community and help the society for and also for future generations with Alzheimer’s and also other domestic diseases.

Grant Belgard: From your perspective, what are the most underrated skills for computational scientists who want to work closely with wet lab teams?

Nataraj Pagadala: With the wet lab teams, actually, we, this is basically a different complex, you know, biology. So I need, you know, I want to work with the people who are well-versed with, especially with the neuroscience one, especially with targeted protein degradation, who has experienced targeted protein degradation in terms of molecular glues, without that, it’s very difficult, you know, to understand, to understand and do the experiments in the, you know, in the laboratory without having a knowledge about the molecular glues are targeted protein degradation. So I prefer the people from this particular background, you know, if you want to work with, yeah.

Grant Belgard: Where do you think molecular glues will realistically be in 10 years? A niche modality or something more mainstream?

Nataraj Pagadala: Yeah, actually molecular glues, as of now, molecular glues are, are in the, in the high priority for different companies and also bigger companies like J&J. So because they are small molecules, as I said, you know, they are brain penetrant, gut penetrant, and also membrane permeable. So molecular glues are the first priority as of now, and also, till now, 24 billions of money was deployed in molecular glue development by different companies and also by different VCs. So molecular glues are the highest priority in, in under the next 10 years, molecular glues is going to occupy number one place compared to traditional drug molecules. Because, you know, as I said, you know, the effect of the molecular glue will be high, very high, 100 times more than a traditional drug molecule. So it is going to, it is the first number one priority in the next 10 years.

Nataraj Pagadala: And also, not only that, in the molecular glues are going to, you know, affect on the disease therapy, especially for the Alzheimer’s in the next 10 years, there is a high chances that a molecular glue therapy will come into existence for Alzheimer’s, for Alzheimer’s, and also help the progression of, you know, and also inhibit the progression of Alzheimer’s. That way, it is a stepping stone for, you know, reversing the Alzheimer’s. If that happens in the next 10 years, trust me that, you know, molecular glue therapy will also reverse the Parkinson’s and also will reverse the ALS and also all the devastating diseases, even the cancer progression. We definitely, we can reverse the cancer progression, and also we can inhibit the cancer progression, you know, 30 to 40 percent. That increases the lifespan of the patient and also the families who are affected with these devastating diseases.

Grant Belgard: Is there a misconception about molecular glues that you wish you could correct for everyone listening?

Nataraj Pagadala: Actually, yes. You know, basically, people think that, you know, molecular glues are very difficult to design. And also, molecular glues have a high serendipity and also off-target toxicity. This is what the people think about molecular glues. But, you know, if you design properly from right from the scratch, you know, and also, we can design a molecular glue with a high target. Because last 10 years, this is what is happening with the molecular glues. Whatever the target is, basically, they are designing, but ending up at the same targets repeatedly every time and showing a degradation. So, because there is some problem in designing the molecular glues. That is the reason why we can design the molecular glues without off-target toxicity, very easily, if you do right from the scratch in a proper way.

Nataraj Pagadala: So, this is the misconception that, you know, molecular glues cannot be designed so easily. That is, that is a misconception there for the different companies all over the world.

Grant Belgard: Finally, if listeners remember just one thing from this conversation, what would you want it to be?

Nataraj Pagadala: Yeah. LigronBio, we are unlocking the undruggable targets for Alzheimer’s and other neurodegenerative diseases with the molecular glues. So, this is where actually we are the pointers in the molecular glue discovery.

Grant Belgard: And how can listeners or potential investors connect with you to learn more?

Nataraj Pagadala: So, basically, through email and also with my website, you know, all the information is given in the website. And, you know, please contact me. If you want any kind of a collaboration, if you want any kind of a help in designing the molecular glues with our TriMatrix Analyzer platform, I’m here to help you in a very effective way. And also, we can reduce the time of research and the cost of your research. And we can design the molecular glue for sure within less than 36 months. So, all the details were given in the website. Please contact me. Or else, you know, my email is npagadala@ligronbio.com. And my cell number is 412-863-3812. Please contact with any of this, you know, medium. You know, I’ll be here to help you as much as I can. Thank you.

Grant Belgard: Nataraj, thank you for joining us.

Transcript of Episode 72: Sophia George

Disclaimer: Transcripts are automated and may contain errors.

Grant Belgard: Welcome to the Bioinformatics CRO Podcast. I’m your host, Grant Belgard. Today we’re joined by Dr. Sophia George, a full professor in the Division of Gynecologic Oncology at the University of Miami’s Miller School of Medicine and a member of the Sylvester Comprehensive Cancer Center. Her lab investigates the genetics and biology of hereditary breast and ovarian cancer and works to close gaps in cancer outcomes across the Caribbean, Africa, and the wider African diaspora. We’ll talk about what her team is doing now, how she got here, and what advice she has for scientists and clinicians working at the intersection of genomics, health equity, and cancer. Dr. George, welcome.

Sophia George: Good morning, hi.

Grant Belgard: Morning. So if you were explaining your lab’s mission to a first-year undergrad, how would you describe the problem you’re trying to solve right now?

Sophia George: Yes, right now is a great question because it has changed a little bit. So what we are ultimately interested in is understanding drivers of cancer and those drivers that lead to more aggressive disease and poor outcomes. And then we take into context what’s surrounding those drivers. So as a molecular geneticist, it’s the only thing about the DNA and sometimes RNA. But now we know that the DNA is not in isolation. Also the RNA is not in isolation and it’s in people. I mean, within cells, within people that are also exposed to factors beyond the genome. And so that’s what we do.

Grant Belgard: What questions are at the top of your list this year and why those?

Sophia George: So questions like, how can we distill spatial and temporal influences on the genome? Meaning spatial, where people are, so geography. And then temporal, how long have they been there? And I’m not thinking thousands of years, but more like tens of years. And how those exposures kind of lead to the signatures that we see, transcriptional signatures that we see in the tissues we’re studying.

Grant Belgard: And what kinds of data are most central for you at the moment? Do you now make transcriptomic, do you now make imaging, clinical, something else?

Sophia George: Yes, everything, everything, which is like, makes us work, makes work very interesting and long, long, long days. So we are looking at epigenetic data using DNA methylation assays, or assays that can tell us about DNA methylation. We’re using epigenomic assays like cut and run and cut and tag. We’re using single cell sequencing assays, transcriptomics specifically, and then spatial assays like COSMX and the APOIA system and a CODEX. And at some point even, I mean, I’m calling names of companies, but that’s how we kind of situate the type of assay and the technology and of course, 10X. So that’s what we use day-to-day in the lab. And then outside the lab in the community, we are also capturing epidemiologic data, survey data, the metadata that’s linked to the individuals that we’re studying the tissues of.

Grant Belgard: What’s a recent result or a signal that genuinely surprised you?

Sophia George: So the more you do, so one of the limitations of the stuff that I do is that one, you have to access the tissue. And of course, clinical data. So part of the metadata is the clinical data. And you’re asking recent, but I would say a while ago, it’s recent in the context of it’s just been put in guidelines. But one of the things that we discovered a while ago is that different populations in the Caribbean have different prevalence of the germline genetic mutations in BRCA1 and BRCA2. And in particular, the Bahamian population have these founder mutations that are really common. So one in four women who have breast cancer or ovarian cancer will have this BRCA1 or BRCA2 mutation specific to that population. The other well-known group are the Ashkenazi Jewish populations or groups. And they have one in 40 people in general, but 10% to 12% who have breast cancer have a mutation in the gene.

Sophia George: So you can hear the differences in these populations. That’s a surprise. So going beyond DNA that you inherit, another thing that we notice is that, at least from the perspective of the work that we’re doing, black women in the Caribbean or people of Caribbean ancestry, and we’ve also noticed there’s, of course, people of West African specifically ancestry. I can’t speak for the entire continent, but I’m speaking from the spaces that I work, have really diagnosed these cancers at a younger age and other populations. Even people with the same BRCA1, not the same identical mutation, but a mutation in BRCA1 and BRCA2. So now it’s collecting samples from all over the world.

Sophia George: We’re seeing that these ancestries with the mutation are a little bit surprising, but it’s good to see it because then we can actually attribute some at least biology, transcriptional biology, tissue biology to the prevalence and the incidence of early age at onset in these populations. So we’re seeing differences in transcriptional profiles that we’ve not yet published, but we’re doing single cell sequencing on hundreds and thousands of tissues from these populations. And so we are starting to see these signals come up, and I’m excited about what the data is going to tell us about the biology.

Grant Belgard: So in ancestry diverse cohorts, what strategies help you separate biology from environment, care access, and other social determinants?

Sophia George: Data, data, data. Really, it’s knowing what you have in the tube and who the people are, where the people are. So it’s putting things in context and why we have to capture that epidemiologic data, the clinical data to discern are we just looking at. I mean, everybody. So for example, I’m studying hereditary breast and ovarian cancer. A lot of my work is focused on the fallopian tubes of people with these BRCA mutations. They have an increased risk of 40% from 27% to like 40% to develop ovarian cancer if you have a BRCA mutation and higher up to 80% you have and for breast cancer. Maybe I’m like skewing the percentages. I think it’s 27% to 60% for ovarian, depending on the gene. OK. So there are other factors that we know are linked to cancer beyond the BRCA. They have an [imputations?] by how many ovulatory cycles or how long women have been ovulating. And that’s the same for breast.

Sophia George: If you have breastfed, if you BMI, increased risk smoking increased risk alcohol consumption. The data keeps telling us how many glasses or no glasses. But nonetheless, alcohol consumption increases your risk. And then a bunch of other things. So when you look at tissue and you isolate the DNA, isolate the RNA, and you’re looking at that signal, then you’re asking, well, for women in West Africa, what age on average do they start having kids? How many kids do they have? The fertility rates are different in the US as even compared to the Caribbean, compared to Africa. So that’s really important to be able to actually see people who are multi-parous. How does a transcriptional profile look compared to people who have one child or no child and no pregnancy or one pregnancy each time that goes to term?

Sophia George: So that is giving us ideas about one just normal physiology of the tissue and then seeing like, well, how can now? So that’s just like normal biology, right? And then we now have the complexity of genomic ancestry, which we know of people in the continent of Africa are the most genetically diverse folks. So we’re not even going down to the single nucleotide polymorphism yet, because we will need tens of thousands. But what we are doing is looking at essentially breaking it down by ethnic groups, self-identified, and also in [?] through the 1000 Genomes Project and others to be able to say, OK, well, people of West Africa, and I’m doing quotation marks, have this signature versus those who are European, or those who are admixed, like in the Caribbean, where we have a little bit of everything.

Sophia George: And one of my PhD students had come up with this logistic regression algorithm and approach to be able to kind of quantify proportion on the amount of African and European ancestry and essentially like a sliding scale and the signature that we see. And so that’s given us an opportunity to be able to disentangle both normal healthy, normal biology of the tissues that we study in the organs and then overlaying that with genomic ancestry. And of course, in the background, I’m determining whether these people have a mutation or not, because that’s also a driver of transcriptional difference.

Grant Belgard: So above and beyond all the biological and social sources of variability, what about the technical sources of variability? Do you think there are issues of collection, fixation, transport, storage, things that you think are currently underappreciated by many people for the impact they have on the downstream analysis?

Sophia George: 1,000 and 20, or maybe 1,200%. That is such a driver. So I should describe a project that we’re doing actively now. We have funding from the Chan Zuckerberg Initiative, where we were funding initially in 2021 to establish the African-Caribbean Single Cell Network. As a proof of concept, can we collect tissues, of course, at the time, snap frozen tissues, single cell tissues that we digest and get single cell suspensions from, I think at the time I started, it was like five or six countries in Africa and the Caribbean and, of course, in Miami. Just the idea of doing that and the premise and collaborating with my peers in those countries and say, do not put things in formalin. And then learning about the process of when tissue gets collected from the OR and taken to pathology and how it gets transported. How long does it sit on the bench? Do we have dry ice? Do we have liquid nitrogen?

Sophia George: That in itself, creating SOPs and changing practice to adapt to collecting tissues that are to be fresh and not just stuck in formalin in writing the OR has been a process on its own that deserves its own one to two, maybe three hour conversation. And you have to do that in each country. And so there is a saturation of the number of samples, right? So instead of saying, well, initially, we’ll digest to 10 and 20. Now we are doing hundreds each country, 400, so that there will be some that fall, right? So you have the outliers. And this is the outlier due to somebody forgot [?] and picked it out. That happens. We can see those added marks. So it takes on training, continuous training of the teams and continuous conversation and monitoring both for tissues and also PBMCs, peripheral blood monocytes, where we started and then we were like, oh, everything is failing.

Sophia George: And it’s because of how long they get kept in the minus 80 or even on the bench, right? So we’ve had to do all of that. And those technical, you can imagine, then over time and in different spaces, you will see these batch effects. So to prevent that from happening and say, we’re sequencing all serially on their own, we have to kind of wait and include samples from different countries in a batch so that when it gets to the lab, whichever lab, they’re trying to decrease the scale of variability.

Grant Belgard: This all sounds very familiar. In my PhD postdoc, we did a lot of postmortem brain work. And yeah, very, very similar challenges. You often don’t have a lot of information on how things were really processed brain bank to brain bank. And in some cases, even within the same brain bank, it will have been processed in very different ways.

Sophia George: Exactly. At the University of Miami, we have several hospitals and clinics where people undergo have to have surgery. So even within our institution, we had to optimize a protocol of transporting samples from the OR to the pathology to the lab. So that would decrease variability within our own health system, because some of them you literally have to drive, like go in a car. Because it’s so far away from the lab, right? It’s not walking distance. So we’ve had to do a lot of optimization.

Grant Belgard: And so if you had unlimited compute, but limited biospecimens, how would you allocate resources across discovery, validation, and mechanistic follow-up?

Sophia George: You’re asking really hard questions. Things that we think about. Okay, so unlimited compute, but limited resources, the tissues. Which is true, which is true, which is a reality. We can’t collect forever. I mean, it would be great to have a saturation of samples and genetic variability. So we would have to do like a test and a validation, right? One of the things that when we decided to scale this project from 15, 15, 15, so 15 fallopian tubes, 15 breasts, 15 prostate samples initially, to now 400, 400, 400, this was to give us room for the technical error, but also hopefully to get to somewhat of a saturation point with the genetic variability. Okay, I know Africa is like completely huge and so much genetic variability.

Sophia George: To test whether if we see something happening in the Ghanaian population and we see differences or similarities in Sierra Leone and in Nigeria because of the geographic proximity. So it would be testing us up, validating another, and then to use, which is something I’m actively thinking about now, use some CRISPR in vitro approach to try to mimic what we’re seeing in the transcriptomics, at least from the single cell perspective. That we still have to go back to modeling. I mean, of course, and I know there’s not like a rambling, but there’s a lot of now in silico things that you can do to mimic like the perturb-seq and all this data, this rich data that’s being generated that we might not need to go into in vitro, but it is always going to be able to say like, these either genetic alterations with this condition is likely increasing risk to develop disease. Can we model this?

Sophia George: And then eventually intercept it somehow, right? Because we know what we think is causing the change. So I would use a lot of tools, artificial intelligence, and generating so much data. Yesterday we saw we had like 1.6 million fallopian tube cells from cells from fallopian tubes just, and that’s only like 85 sample, no, a hundred and something samples, right? So it’s not, and we’re planning on doing this for like 300 to 400 samples per tissue type. And so it’s, we’re going to have a lot of data to inform on what it is that’s happening.

Grant Belgard: Are there computational approaches that you’re excited to scale up or to apply on this really large data set, right? Because oftentimes there are things that in principle people would like to do, but when, you know, you’re looking at data sets that were typical five years ago they just didn’t have the sample size to do it. But with the sample sizes you’re now working or that you’ll be getting, it might open the doors.

Sophia George: Yeah, so I really am excited about working with informaticians who want to use or who are using, I mean, we can’t really avoid it now at different neural networks, LLMs to be able to give us more information and the information, like I already know that my ability to ask questions about the data to look in front of me is limited because I cannot infer the relationships by just looking at it of cells amongst themselves and how the genome is interacting with the transcriptome beyond like the exons, like beyond the exons, right? So how, like, I am excited and I want the data to talk to me and to tell me what is happening. And so I look forward every day. I’m like, okay, what new packages out there?

Sophia George: What new algorithm did somebody come up with to the data that already exists, like in Cell by Gene and Human Cell Atlas, for example, talk to us, like, what is it telling us that I have the limitations of not even being able to ask? So I’m excited about that.

Grant Belgard: When you look at the literature on aggressive breast and gynecologic cancers, where do you see the biggest gaps that bioinformatics could realistically fill in the next five years?

Sophia George: I want more integration of the data. I want more what is happening, which these samples are hard to find, right? But they’re not, they exist. And what is the least amongst, as you asked me before, what is the least amount of data we can put in to be able to infer causality or even a relationship to disease progression? And then of course, on the other side is, well, how do we learn about all the data that we have? What do we learn from it in response to treatments? Knowing that, okay, this genetic signature from this genomic background will likely not respond to like pharmacogenomics and with the transcriptomics will likely not respond to drug X because we have modeled this a thousand times. This we know for sure. These are the questions that I would like answered and with what we already have and all the data that’s been generated like exponentially every day.

Grant Belgard: So when thinking about prevention in hereditary cancers, what does precision prevention look like in practice?

Sophia George: It’s just the old fashioned identify people at risk and then intervene with screening. And of course then there are cooler ways where, so how do you identify? So you could ask how do you identify the person in the first place, right? So how do we identify people who don’t even know that they are at risk or not aware? Yes, mom had breast cancer or ovarian cancer or pancreatic cancer and you think, oh, you know, grandma had that cancer and then you just kind of like, yeah, all people as we age, we get cancer because this cancer is the disease of the aging. Oh, it used to be so. So what tools again, computational tools, can we use to identify these individuals based on the data that they’re putting out there who would benefit from screening, genetic screening? And so that’s the population side.

Sophia George: And then of course the molecular side is of all the data that I’m generating, what are the ways that we can use small molecules to prevent disease?

Grant Belgard: If you had to bet, what’s the most likely near-term translational payoff from your current line of work? You know, is it more risk stratification, earlier detection, therapy selection, something else?

Sophia George: Risk stratification, I’m excited about some things that I brought some folks together to think about in terms of how do we use the data that I’m generating in the real world because they’re real people with real data. And so risk stratification is, you said one, but that’s one on that side. And then there’s a clinical trial that I’m co-principal investigator of where we’re looking at targeted therapy in these populations in three countries, the United States, Nigeria, and the Bahamas to be able to better identify individuals who will respond to these already FDA-approved drugs versus those who would not. I’m excited about that. That’s like long-term because the clinical trial just begun this year, but that’s something that I’m excited about learning.

Grant Belgard: Do you know when that’ll be finished?

Sophia George: Well, it’s a five-year clinical trial. So it just started today, not today, this year, so in five years, but we will be obviously getting data as soon as we see recurrence or response. And of course, you can’t make a conclusion from one person, but it is the fact that we get to do this study and all the components of it, of course, multi-omics and all the fancy things, all the tools, we’re doing all the tools, using all the assays that are available to us now and samples that we banked that we can do things in the future to be able to really go deep in understanding what’s going on. So that’s like a ways away, but in the meantime, it’s a re-stratification and again, integration of all the things that’s what we’re doing.

Grant Belgard: Something to look forward to, yeah.

Sophia George: Yeah, I’m excited. It was like we’ve done a lot of building and now we get to, again, ask really interesting questions and then hopefully have tools to help us resolve things that we don’t even, are not aware of.

Grant Belgard: Yeah, it’s kind of the, you know, biology equivalent to some of these big particle physics experiments, right? It can take a very, very, very long time to get the infrastructure in place and then you run the experiments and get the answers.

Sophia George: Yes.

Grant Belgard: So pivoting now to your own career, what first pulled you towards gynecologic oncology and hereditary cancer research?

Sophia George: Quite honestly, it was, I did a job after my PhD. I did a PhD in molecular genetics, molecular medical genetics and it was on engineering embryonic stem cells and differentiating embryonic stem cells on the cardiovascular system and looking at embryonic development and vascular genesis, angiogenesis. I wanted to do something with humans and I had considered going to medical school. I had applied to go to medical school, I got in and I had just had my son at the end of my PhD and I wanted to take a breather between all those decisions, between making all these decisions and so I applied for a job and I applied for a job to work at a biobank and the person, director of the biobank at the time, she said, but you’re too qualified, you’re overqualified. What is wrong with you? And I was like, I just want a job for a minute just to like not do anything science-y.

Sophia George: And so she offered me equivalent of a postdoc position in her lab and she helped focus, she wanted me to establish cell lines from fallopian tube and [epithelial?] cells from women who were undergoing [risk-reducing?] surgeries because at the time it had just been published and not yet published that the fallopian tubes were a likely site of origin for high rates of ovarian cancer because she’s a pathologist and her scholarship was in hereditary ovarian cancer before it was even a thing like in the context of fallopian tubes. So that’s how I got started. And then the following year, I was always interested, I’m from the Caribbean, I should state, all those listening, wondering where is that accent from. I’m from a tiny island called Dominica in the Caribbean, not Dominican Republic.

Grant Belgard: Dominica is always advertising the citizenship by investment on the planes, right?

Sophia George: Oh my goodness.

Grant Belgard: Every time you fly British Airways or something.

Sophia George: Okay, fine. So I’m from that island. We only have 70,000 people so we can afford to have visitors come. Okay. And so I’ve always been interested in health of the population, mine, I guess, and looking back. And so I got a scholarship to go to school in Canada, did my undergrad, did my PhD at U of T and during my PhD, I got to go to Venezuela with the UN and at the time, the Centre for Bioethics at the University of Toronto. And so I got exposed to thinking about doing genomics in the Caribbean and Latin America. And I had the opportunity to meet people from the Caribbean at the time, got invited to go to the Bahamas and say, oh, by the way, let’s think about genomics in the Caribbean. And I’m working for hereditary- I’m working on a project on hereditary ovarian cancer. And they said, oh, we also have this in Bahamas. And I was like, what do you mean you have BRC in Bahamas?

Sophia George: Like, it’s not a Bahamian thing. It’s a Jewish thing because I was in Toronto and that’s who had the BRCs. And that is how I got really fascinated about our population many years ago.

Grant Belgard: Just geographically, it seems being based in Miami makes a lot of sense. You’re, you know, a short flight or ferry right away.

Sophia George: Exactly. And that is my mentor. So I was in Toronto at the time and my mentor, the person who became my mentor, who was leading the study. So I said to the people when I was in Canada and I’m in the Bahamas. They’re giving a talk. Who is leading this research? And they’re like, oh, someone at the University of Miami and someone in Toronto, Steven Narod and Judith Hurley was at the University of Miami as a medical oncologist. And I got introduced to them. And she is a phenomenal woman who allowed me to ask questions and introduced me to everyone. And now I lead this work, right? But that’s how I got in to studying hereditary ovarian cancer.

Grant Belgard: So speaking of mentors, how did you find mentors and what made those relationships work?

Sophia George: Oh, wow. So Judith was serendipitous, I guess, because as I said, I was in the Bahamas and they said who might I reached out, not necessarily for her to be my mentor, but to see if I could learn more about this study. And she was magnanimous and generous. And I learned so much from her about how to engage with, who do you need to engage with to have impact. There’s always more people, but for sure, the people treating, the doctors treating the patients, you cannot, they’re not, or not to be a bystander in the work, right? Because they’re the ones that are going to see the patients to implement the things that we will eventually find and discover. So she, her personality allowed her to develop into my mentor, to learn and navigate the space.

Sophia George: Pat Shaw, who was my postdoc mentor and lead of the biobank and a pathologist, she ended up being a mentor because she knew so much about the system that we were in and what I was trying to do, quite frankly, as a woman. And it happened to me that I’m a woman of color and not that she was a woman of color, but being a woman in the space, in academia and allowing me to meet her networks and be introduced to them. So I’ve since then identified people that helped me in specific needs, areas of growth. So I tell my folks all the time that I mentor that you can have multiple, and peer mentors are really important. How we can help each other, drive each other, but also again, identifying folks for me who fill a gap and also have some redundancy.

Sophia George: So cheerleaders, supporters, folks who can help me plan and navigate, those have been factors in how I identify folks who might wanna spend time with and learn from.

Grant Belgard: What skills have you found hardest to learn on the job that you wish training programs taught more explicitly? People management, we don’t train the trainees.

Grant Belgard: I think that that is the most common answer I get when asking academics this question, right? Cause you’re promoted cause you’re good at doing science, right? And I guess the assumption is just, you pick up people management on the way.

Sophia George: Yeah, like somehow, right? We know about the DNA, RNA, protein, whatever molecule that we’re studying or trends that if you’re a population scientist, but how do you manage people? I mean, I guess people who do business and other things, they get to learn that.

Grant Belgard: Oh yeah, there are explicit training programs, coaching programs, absolutely, yeah.

Sophia George: Really? No, you learn that, you get to learn that like when you have a lab with people in it already and you’re like, wait a minute, I think I need to learn how to do this. So that, and then budgeting, finance. Although we have people that help us with the finance, but it’s not the same way of conceptualizing how much this project is really going to cost. What are all the factors involved that would cost money? And how do we identify sources of flows beyond and actually being creative about whom you collaborate with and how you do the collaborations. Again, institutions have some of those things, but we don’t get to think about that pre you come into it and then you hope that you find mentors or honest brokers that can let you know that this is happening and that’s an option beyond like thorough funding and how you partner with industry, different types of industry, all those things.

Grant Belgard: Yeah, the budgeting and project management’s a good point. I recall my postdoc advisor had spent some time in management consulting before his MD PhD and he really would use that pretty regularly and it really gave him a leg up in thinking about exactly what you said, what’s the true all in cost of a project, right? Because it’s a lot more than just what you have in the grant and then the time and thinking about recruitment and all that.

Sophia George: I mean, the time, the time, the time, the time. We are on 40 hour week of 60 hour week, whatever the week is, it’s never enough. And especially when you’re doing projects at scale where you are enabling people to lead, you have course when you are at different sites, you have site PIs and they have expectations and so on. But if you’re driving some parts of the science, it takes a lot of time to get everybody on board and a continuous training, all those things are not budgeted for. You know, there’s no line. I’m really, is there a line? Some people are like, yes, I put a line, but that line is never the true line, right? But it’s well worth the efforts of all the things. But yeah, it’s the budgeting, the project management.

Grant Belgard: How have collaborations across institutions or across countries changed the way you do science?

Sophia George: It has changed it significantly. So how? One, different systems, different cultures and practices and how to engage and expectations. Expectations vary independent of the cost. So even if you have a budget, some people want you to be fully involved. Some people want you to be not fully involved. Expectations, not talking about publications, but relationships, like what, how are these relationships built and sustained? They vary by country and they vary by partner, collaborating partner. And so for me, I have projects in, where we, in one region, three different languages. So projects in, oh four actually, Dominican Republic, in Haiti, in Benin Burkina Faso and English. So that’s four languages. And so, and each system, each country is different. And even within country, the institutions are different, different infrastructure.

Sophia George: So, and different questions that they want to ask, different priorities and how they want to ask the questions. So one disease might be more important than another, even within the same organ. And so making sure that, I call them informed believers on board, you have to also acquiesce, which is why collaborations work like the give and the take, or the give and the give, right? What it is that are you fundamentally interested in? Because even if I’m interested in like ovarian cancer, a lot of my collaborators, ovarian cancer is relatively rare compared to other diseases in some parts of the world. So they want to focus on prostate. They want to focus on cervical cancer. They want to focus on some rare disease that only is impacting their population, where I’m interested in the other part of the tissue.

Sophia George: And so how do we ask a robust question scientifically and have everybody, according to COVID, win-win, right? Like always it’s a win-win. So it’s a lot of interplay. And so the science that you see and the science that I’m thinking about is not like linear.

Grant Belgard: What non-technical skills do you find most accelerate progress in community-engaged genomics and in navigating multinational consortia?

Sophia George: One non-technical skills, communication. Communication has been a big, has been an important factor. Humility, I guess, is a behavior. I don’t know if it’s a skill, but it’s necessary. So communicating, being transparent, which facilitates the communication and humility, those things have allowed me to be with my partners on the ground forever, have allowed me to be able to do what I’m doing.

Grant Belgard: If you were advising a PI on setting up a multi-site cohort from scratch, what would you emphasize in governance and quality control?

Sophia George: So governance, setting up a team of folks at individual sites who have been trained and understand the biology enough that the representatives of you versus just managing. And then having harmonized system to collect and track whatever is going on. Like if you’re collecting blood, whatever you’re doing. And of course, optimizing protocols locally. So what protocol you write here or wherever you are is not going to necessarily translate to the T in a different setting that you do not want people to fill in gaps without your knowledge. So it’s like shopping the protocol, workshopping the protocol in each site versus disseminating one protocol and assuming that everybody’s doing the same thing.

Grant Belgard: I feel like that’s pretty universally applicable advice when you try to do anything across different sites in science, outside of science. How do you personally protect time to do deep work?

Sophia George: I block my calendar. So this year I’m interim associate director for the Center for Black Studies at the University of Miami. An interesting year to take up that role, but this is the year. And the center is on another campus. And when I go there, I can be quiet because sometimes nobody knows that I’m there, which is like the best thing. I have to be away from my home often and or my lab office and the lab in a very quiet space. My best work is in the middle of the night, but it’s not sustainable because then I wake up late and I don’t get enough sleep, et cetera, et cetera. Or I wake up early and I don’t get enough sleep when it’s super quiet. So for me, it’s just blocking my calendar and finding peace, like somewhere quiet so that I can think. I can read a paper from beginning to end and think.

Grant Belgard: And what advice would you give your first year PI self?

Sophia George: Oh, Lord, don’t be afraid to pursue the thing that you think is hard. Don’t be afraid. And be bold. Don’t be afraid. Because at once I was considered very timid and shy and sit in the back of the room. And I know that affected my ability to do more sooner.

Grant Belgard: So speaking of being bold, if you could place one big bet in your field and you had to wait 10 years for the readout, what would you fund?

Sophia George: In my field. My field is like, I mean, I’ve developed a few fields. We still, surprisingly, we still don’t have enough people sequenced. Surprisingly, we still don’t know enough between the transcriptome and the DNA, the genome. So, you know, these projects that I’m doing, we need more. We need to get to saturation. So 3,500 single-cell samples from different bodies is not enough. Even if that leads to, I don’t know, 35 trillion cells, I don’t know how many, 10,000, let’s say 10,000 cells, times 3,500, whatever that math is, 35 million. It’s not enough. No, so it’s gonna be three billion cells. It’s not enough. It’s not enough. It’s not even reflective of the number of people in the world. Right. So it’s not enough. It’s not enough. So I would do that. I’ll do more of that. And I would do like deep work, deep.

Sophia George: So the whole human kind of work where you’re not just capturing the single-cell, the RNA, but you’re capturing the epidemiologic data. You’re capturing that metadata that puts context with that piece of tissue or RNA, protein, metabolome, like the molecule, you know, that you, you know, whatever your measure is, that there is significant metadata to make it make sense, to contextualize it. So I would be doing that.

Grant Belgard: I don’t think any of our bioinformatics-interested listeners would disagree with, you know, more data and better metadata, right? Two things people always want.

Sophia George: I mean, it opens the doors to so many, you know, new additional methods and so on that can be used. King and queen. I said king. Metadata is king, but it’s also queen. Like it’s, it’s non-gender. It’s important.

Grant Belgard: So where can our listeners follow your work and your lab’s updates?

Sophia George: Oh boy. So I’m supposed to be updating my website. I post sometimes on Instagram. Sophia HLG and publications. I, yeah, kind of, I know it does, it sounds anticlimactic, right? But yeah, when we travel, we post and of course publications here and seeing the work that we’re doing. Some of it, they all look now and be like, well, this is like all epi stuff, but while we’re building the, and Grant knows and sees the different types of assays that are coming through, it takes time to get these types of rich data and to make, I’m not a, I don’t want to make fast and dirty conclusions. So the metadata and the clinical data is really important to put context with these populations and samples that we’re studying.

Grant Belgard: Thank you so much for joining us today. Really appreciate it.

Sophia George: It’s been fun.

Grant Belgard: Thank you.

Sophia George: Thank you for having me. Thank you.

Transcript of Episode 71: Christiaan Engstrom

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Transcript of Episode 70: Joanne Hackett

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